Positioning Filgotinib in the Treatment Algorithm of Moderate to Severe Ulcerative Colitis

Abstract Background and Aims Filgotinib is a small molecule that selectively inhibits Janus kinase [JAK] type 1. It is already approved for the treatment of rheumatoid arthritis and is being evaluated for the management of patients with moderate to severe ulcerative colitis [UC]. The purpose of this review is to provide an overview of the currently available data on filgotinib and to define how to position this new drug in the treatment algorithm of patients with UC. Methods The Pubmed, Embase and Scopus databases were searched up to June 25, 2021 in order to identify studies reporting efficacy and safety data of filgotinib in patients with UC. Results Data from a phase III study enrolling UC patients with moderate to severe disease show that filgotinib is effective with a reassuring safety profile. Filgotinib treatment is not associated with a greater risk of thrombosis and herpes zoster infections compared to other JAK inhibitors. However, animal studies reported impaired spermatogenesis and histopathological effects on male reproductive organs, making it necessary to deepen this aspect in dedicated human studies. Conclusions Filgotinib is an effective and safe drug for treatment of both biologic-naive and biologic-experienced patients with moderate to severe UC and may soon be available.


Introduction
Ulcerative colitis [UC] is a chronic inflammatory bowel disease [IBD] with a remitting and relapsing course. 1 In the last few decades, the therapeutic options for patients with UC have substantially increased with the introduction of biological therapies. Several drugs are currently available including tumour necrosis factor [TNF] inhibitors [golimumab, adalimumab and infliximab], integrin inhibitors [vedolizumab] and inhibitors of interleukin 12-23 [ustekinumab]. 2 However, up to 30% of patients fail to respond to initial therapy and roughly 50% lose response over time, with 10% still requiring surgery. 3 Several efforts have been made to develop new molecules and to address this unmet medical need. 4 In 2018, tofacitinib, a small molecule, was approved by the Food and Drug Administration [FDA] and the European Medicines Agency [EMA] for the treatment of UC. 5 Tofacitinib is an oral drug and has a completely new mechanism of action. 6 Unlike biologics that specifically block a certain target, tofacitinib interferes with the janus kinase [JAK]/signal transducer and activator of transcription [STAT] pathways. JAKs comprise four intracellular tyrosine kinases [JAK1, JAK2, JAK3 and TYK2] which regulate different intracellular functions including inflammatory mechanisms. 7,8 They stimulate the activity of lymphocytes and cytokines and the production of mucus and have a relevant role in haematopoiesis and viral defence. 7 The inhibition of JAK allows us to modulate different components of the inflammation at the same time as contributing to a reduction of the inflammatory state. 7,8 Tofacitinib inhibits JAK1 and JAK3 but at high concentrations it also blocks JAK2 and TYK2 and can be considered a pan-JAK inhibitor. 7 Phase III clinical trials have proved the efficacy of tofacitinib in patients with moderate to severe UC. [9][10][11][12] However, concerns about the safety profile persist with regard to a reported increased risk of high lipid concentrations, thromboembolic events and herpes zoster infections. [13][14][15] Interestingly, growing evidence shows that JAK1 is the pathway most implicated in innate and adaptive immune responses. 16 On the other hand, JAK2 is related to erythropoiesis and thrombopoiesis, JAK3 to lymphocyte proliferation and immune homeostasis, while TYK2 is associated with antiviral responses. 16 It is therefore plausible that the selective inhibition of JAK1 may be associated with an improved safety profile and a reduced rate of adverse events. This rationale led to the development of filgotinib, a selective inhibitor of JAK1. Filgotinib proved to be effective for the treatment of rheumatoid arthritis and is approved for this indication. 17 The efficacy and safety of filgotinib has also been tested in the field of IBD. 18,19 The purpose of this review is to provide an overview of the available evidence on filgotinib in patients with moderate to severe UC in order to better define how to position this new small molecule into the therapeutic algorithm of UC.

Review criteria
We searched the Pubmed, Embase and Scopus databases up to June 25, 2021 in order to identify studies reporting efficacy and safety data of filgotinib in patients with UC. The following search terms were used: 'filgotinib', 'JAK inhibitors', 'anti-JAK', 'selective JAKi' combined with 'ulcerative colitis', 'UC', 'inflammatory bowel disease' and 'IBD'. Only articles published in English were considered. Three authors [F.D., S.D. and L.P.B.] independently reviewed titles and abstracts to identify eligible studies. The full texts of the selected articles were examined for inclusion, and relevant references in their lists were hand searched to identify studies missed by the electronic search. Abstracts and articles were included based on their relevance.

Pharmacokinetics and pharmacodynamics
Filgotinib has a 5-fold higher potency of inhibiting JAK1 compared to JAK2, JAK3 and TYK2 and can be considered a selective JAK1 blocker 17 [Table 1]. Filgotinib is rapidly absorbed and its median peak plasma concentration [C max ] is reached 2-3 h after the drug dose. 17 Its mean half-life is approximately 7 h. 17 No difference in filgotinib concentrations was found based on drug administration in combination with high or low fat or fasting meals. 17 Thus, food does not affect filgotinib concentrations and the drug can be given with or without food. 17 Filgotinib binding to human plasma proteins is low [55-59%] suggesting that this small molecule has no preferential distribution within blood cells. 17 Filgotinib is predominantly metabolized by carboxylesterase 2 [CES2] and CES1, in a non-CYP450-dependent fashion, leading to the production of its active metabolite, GS-829845, with similar JAK1 selectivity, which is approximately 10-fold less potent, but a 16-20-fold higher exposure than the parent molecule. 17 Elimination of the drug is mainly urinary [85%], while a small part is eliminated in the faeces [15%]. 17 No clinically significant differences were detected in patients treated with filgotinib or its metabolite based on bodyweight, gender, race or age. 17 17 The effects of the drug on patients with end-stage renal disease [CrCl <15 mL/min] and severe hepatic impairment [Child-Pugh C] have not been studied, while both filgotinib and its metabolite have not been associated with prolongation of the corrected QT interval. 17,20 Regarding the interactions between filgotinib and other molecules, it should be emphasized that filgotinib does not significantly inhibit or induce cytochrome P450 [CYP] enzymes or UDP-glucuronosyltransferases, which are generally involved in drug interactions, suggesting a low risk of interaction with other drugs. [21][22][23][24]

Efficacy and safety in UC
The efficacy and safety of filgotinib were tested in a randomized, double-blind phase 2b/3 study [SELECTION trial] enrolling patients with moderately to severely active UC. [25][26][27] The trial consisted of two induction studies and one maintenance study. In the induction study, both biologically naive patients and those who had previously failed biologic therapy were eligible. In total, 659 biologic-naïve and 689 biologicexperienced patients [of whom 43.1% had experienced failure of both a TNF antagonist and vedolizumab] were included and randomized 2:2:1 into three groups [filgotinib 200 mg daily, filgotinib 100 mg daily or placebo]. 27 The primary endpoint was clinical remission at week 10, defined as Mayo endoscopic subscore ≤ 1, rectal bleeding subscore = 0, and ≥ 1-point decrease in stool frequency subscore from baseline to achieve a subscore ≤ 1. Clinical remission at week 10 was achieved in a significantly higher proportion of biologicnaïve [ 28 This improvement remained stable over time throughout the maintenance phase. 28 Moreover, greater improvements from baseline in quality of life based on the 36-item short form survey 36 [SF-36] score were experienced in both biologic-naive and biologic-exposed patients treated with the experimental drug compared with placebo both after 10 weeks of induction therapy and after 58 weeks of maintenance therapy. 29

Safety in other immune-mediated inflammatory disorders
Most of the literature evidence on filgotinib comes from rheumatological studies. In the EQUATOR trial, a randomized, double-blind, placebo-controlled phase 2 trial enrolling adult patients with active moderate-to-severe psoriatic arthritis, no significant difference in the rate of treatment-emergent adverse events [57% vs 59%] and serious adverse events [2% vs 2%] was detected between filgotinib and placebo during the study period. 31 Nasopharyngitis and headache were the most frequent adverse events. Similarly, the same proportion of adverse events were found in patients with ankylosing spondylitis after being randomized to take filgotinib or placebo [31% vs 31%]. 32 Nasopharyngitis was the most frequent adverse event, while no cases of herpes zoster infection or neoplasia were reported. One case of non-serious deep vein thrombosis occurred in a 53-year-old patient with a factor V Leiden mutation receiving filgotinib therapy. Several studies investigated the safety of filgotinib in patients with rheumatoid arthritis. 31 Importantly, animal studies reported that some male subjects treated with filgotinib had minimal to moderate testicular atrophy/degeneration in the epididymis. 17 The FDA recently requested data to investigate whether filgotinib has an impact on sperm parameters. 39

Positioning filgotinib in UC
In recent decades, the leitmotif of pharmacological research has been the need for effective but at the same time safe drugs. The development of JAK inhibitors represents a revolution in the treatment of patients with UC. Filgotinib is an innovative drug and could represent a valid alternative to currently available molecules. It has a rapid mechanism of action and oral administration is generally well accepted by patients. 17 41 In patients with UC, on the other hand, there is little evidence on this topic. This can be explained by the lack of head-to-head trials that provide a direct comparison between drugs. In the absence of a commonly accepted therapeutic strategy, it is likely that therapeutic decisions will be increasingly individualized and tailored according to the patient's characteristics [ Figure 1]. In elderly subjects or those with a previous history of malignancy, the use of vedolizumab, a drug with a selective gut mechanism, may be preferred for its safety profile. Conversely, the benefit of anti-integrin in those with extraintestinal manifestations [e.g. joint symptoms] is unclear. 42 In this context, TNF alpha inhibitors, ustekinumab or JAK inhibitors may be indicated. JAK inhibitors are not recommended during pregnancy as they are associated with a risk of teratogenicity. 43 On the other hand, TNF blockers are commonly used during pregnancy and the first efficacy and safety data of vedolizumab and ustekinumab in pregnant women have been reported. 44,45 The rapidity of action of filgotinib could justify its choice given that as early as from 4 weeks of treatment it is associated with significant clinical improvements leading to a better quality of life. The lack of immunogenicity is another point in favour of filgotinib, as unlike biological drugs its efficacy is not affected by drug concentration and the development of anti-drug antibodies. Of note, patient preference is another variable to consider in the therapeutic decision-making process. Most UC patients are young of working age so infusion medications may be challenging and limit their quality of life. 46 Some patients are afraid of needles, hindering the use of subcutaneous drugs. 47 The use of oral drugs could reduce the indirect treatment costs as it could reduce hospital admissions and overcrowding by preventing the risks of viral infection in the current global pandemic context. Finally, filgotinib could be used in both biologic-naive and biologic-exposed patients. It could represent a valid alternative to tofacitinib, particularly in those who have an increased thromboembolic or infectious risk [ Figure 2]. Filgotinib could be used in steroid-resistant and steroid-dependent patients or those unresponsive to immunosuppressive drugs. To date, comparative data between immunosuppressants and small molecules are not available but anti-JAK agents may be preferred due to their ability to induce disease remission and the questionable handling of immunosuppressants, which require periodic biochemical tests and have been associated with an increased risk of haematological disorders and malignancies. [48][49][50] Oral administration Cost-saving of infusion suite visits

Filgotinib vs other JAK inhibitors
Most of the data comparing JAK inhibitors come from rheumatoid arthritis studies. A network meta-analysis including five randomized clinical trials with over 1500 patients with rheumatoid arthritis compared the efficacy and safety data of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy. 51 All the small molecules proved to be effective. 51 Interestingly, peficitinib had the highest probability of being the most effective drug, followed by filgotinib and then by tofacitinib, upadacitinib and baricitinib. No significant differences in the adverse event rate were recorded. 51 Sung and Lee investigated the efficacy and safety of tofacitinib, baricitinib, upadacitinib and filgotinib in disease-modifying antirheumatic drug-naive patients with rheumatoid arthritis. 52  In addition, most diagnosed herpes zoster infections were mild to moderate in severity. However, it must be emphasized that further studies are needed to confirm the link between drug selectivity and safety. Furthermore, the drug selectivity is lost with the dose increase. 7 To overcome this limitation, patients who are candidates for JAK inhibitor therapy should be vaccinated for herpes zoster before starting therapy in order to minimize the risk of infection. 56,57 Finally, an increased risk of thromboembolic events has been recorded in rheumatoid arthritis patients with cardiovascular risk factors who are undergoing tofacitinib therapy. 58 Following this finding, the regulatory activities of the FDA launched a warning stressing the need to evaluate the risks and benefits of tofacitinib in patients with high thrombotic risk and imposing the use of the lowest drug dosage available in this setting. 58 As noted above, few cases of pulmonary thromboembolism have also been reported in patients treated with filgotinib, but whether this is a drug class adverse event or due to inhibition of a specific pathway is not yet known and needs to be confirmed in the long term.

Discussion
Treatment scenarios for UC patients are rapidly expanding. The need for safer drugs has led to the development of selective drugs in order to reduce the occurrence of side effects. In addition, increasing attention is given to the rapidity of action of the drug and to the administration route, aiming at providing a benefit in the shortest time and improving the quality of life of patients. Filgotinib is a second-generation JAK inhibitor, which is administered orally and has a rapid mechanism of action. Pending long-term data, the available safety and efficacy data of filgotinib are reassuring. Thus, filgotinib, as well as other selective JAK inhibitors, could hopefully represent an evolution towards rapid and effective oral therapies with an improved safety profile. The ever-increasing number of available drugs underlines the need for head-to-head trials that directly compare the efficacy and safety of two different molecules in order to clarify which is the best option for the patient. In this context, it is likely that therapeutic decisions will be progressively personalized and tailored based on the patient's clinical characteristics. Soon, the combination of multiple molecules acting on different inflammatory pathways could become more common. Some case series reporting the use of combination therapies between biologics and small molecules show that this approach is feasible in the IBD field. 59,60 On the other hand, there is no evidence regarding the association of multiple oral small molecules. More data could come from the development of national and international registries as occurred in rheumatology, especially for patients with rheumatoid arthritis, allowing for a greater understanding of the disease. 61 A recent initiative by the European Crohn's and Colitis Organization [ECCO] was the creation of The United Registries for Clinical Assessment and Research [UR-CARE] platform, which is an online international registry designed to collect IBD patients' records. 62 The development of large national and international registries including patients with similar characteristics could be essential to improve knowledge about IBD and define the best management of patients. Another relevant aspect to consider is the price of the drug along with economic issues. The median price for each patient per year after filgotinib treatment is estimated at £10 508 based on the list price. 63 The exact cost for the annual treatment of a patient with UC is not yet known, but much will also depend on national reimbursement policies. In fact, national reimbursements will determine a different cost from country to country and could justify a country-specific positioning of filgotinib based on cost-effectiveness principles.
In conclusion, preliminary data show that filgotinib is an effective and safe drug for treatment of both biologic-naive and biologic-experienced patients with moderate to severe UC and may soon be available. Although further studies are needed for its approval by regulatory authorities, the prospect of using a highly selective drug is attractive and could usher in a new era based on individualized treatments.

Supplementary Data
Supplementary data are available at ECCO-JCC online.